ABCA1: In addition to increased HDL-C, overexpression of ABCA1 in C57Bl mice (ABCA1-Tg) fed an athero diet, decreased plasma cholesterol, apoB-containing lipoproteins (B-Lp) and apoB. Compared to controls, ABCA1-Tg mice had decreased plasma levels of total cholesterol, non-HDL-C, and apoB and increased plasma levels of HDL-C and apoA-I. FPLC confirmed a decrease in nonHDL-C and increased HDL-C in ABCA1-Tg compared to controls. This unanticipated beneficial effect of ABCA1 overexpression on the pro-atherogenic B-Lp significantly contributes to the marked decrease in diet-induced aortic atherosclerosis in ABCA1-Tg mice. To identify the mechanisms by which ABCA1 increased HDL-C and decreased the B-Lp, we performed kinetic studies in ABCA1-Tg and C57Bl mice for 15 wks on the pro-atherogenic diet. Compared to controls, the fractional catabolic rates (FCR) for ABCA1-Tg injected with 3H-CEt HDL and 125I-ApoA-l HDL decreased while the apoA-l production rates were similar. Thus, the increased plasma HDL levels in ABCA1-Tg is due to delayed catabolism of apoA-I. In contrast, 131l-apoB-Lp kinetics demonstrated markedly enhanced catabolism of B-Lps in ABCA1-Tg compared to control mice and similar PR. Direct quantitation of apoB production rates by the 35S-methionine/triton method confirmed similar apoB production rates. Western blot analysis revealed a 2-fold increase in hepatic LDLr expression. Thus, the decreased B-Lp in ABCA1-Tg is due to enhanced LDLr-mediated B-Lp catabolism. In summary: 1) ABCA1 increased HDL-C by decreasing HDL catabolism and decreasing B-Lp by increased B-Lp catabolism; 2) The LDLr plays an important role in facilitating ABCA1-induced decrease in B-Lps; 3) ABCA1 modulates not only HDL but also B-Lp metabolism resulting in a protective lipoprotein profile that decreases diet-induced atherosclerosis in C57Bl/6.